With this K24 Career Development Award I am seeking to enhance my opportunities to engage in translational, investigator-initiated research and to mentor physician-scientists entering a career of clinical investigation. I have devoted much of my career to systemically developing immune- and cell-based therapies in the laboratory and in the clinic and have a proven track record as a mentor for residents, fellows and junior faculty pursuing careers in cancer-related clinical investigation. If I should receive this award, I will focus my clinical activities on translational research in patients with advanced renal and prostate malignancies, decrease my patient and administrative responsibilities to one-half day per week, and dedicate my time to the mentoring of new clinical investigators. My immediate research objectives include studies to reverse tumor-mediated immunosuppression and to induce therapeutic antitumor immunity in cancer patients using antigen-loaded dendritic cell vaccines. The first part of this investigation will explore a novel and promising strategy to eliminate immunosuppressive immature myeloid suppressor cells (ImC) in metastatic renal cell carcinoma patients (RCC). In Aim 1, we will develop new technologies enabling us to define, track and monitor ImC in the peripheral blood of RCC patients and develop methods to abrogate their immunosuppressive activity by using differentiation agents. In Aim 2, we will test whether these insights can be translated into clinically relevant human settings by conducting a phase I/I I study in which RCC patients will receive escalating doses of the differentiation agent ATRA, followed by vaccination with antigen-loaded DC. In Aim 3, we will perform thorough immunological and clinical monitoring to determine the biologic and clinical effects of such combinatorial regimen. This novel approach may advance rapidly into phase II clinical trial testing by directly addressing the question of clinical benefit in advanced cancer patients. Alternative strategies to reverse ImC-mediated immunosuppression include inhibition of reactive oxygen species or nitric oxide, possibly acting synergistically with vaccines to enhance immunologic reactivity. I have extensive collaborations with basic and clinical scientists within and outside the Duke Campus through my own NIH- funded research grants and have successfully mentored numerous investigators, including investigators involved with current projects. The projects in this K24 application represent clearly defined paths for young investigators to pursue patient-oriented clinical research under my guidance. These mentoring activities are strongly supported by Duke leadership and represent a unique training opportunity in translational medicine for the next cadre of clinical investigators. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]